My career goal is to successfully lead multidisciplinary translational research in critical care, focusing on the relationship between long-term health and episodes of acute illness, such as community-acquired pneumonia (CAP). I have the support of a leading Department of Critical Care Medicine at the University of Pittsburgh, uniquely suited for multidisciplinary research, and the commitment of an experienced and successful mentor, Dr. Derek Angus. Under his mentorship, I have assembled an advisory committee of a genetic epidemiologist, biostatistician, microbiologist, molecular biologist, and geriatrician. Training will complement my research proposal and include formal coursework and hands-on laboratory experience in each discipline. My research proposal focuses on susceptibility to CAP. My preliminary data have helped demonstrate that CAP occurs due to a complex interplay of clinical risk factors, genetic markers, circulating inflammatory molecules, and the efficiency of the immune system. In line with the NIH Roadmap initiative to prevent disease by improved understanding of such complex biological systems, I propose two parallel aims. First, I will develop and validate a multi-attribute pneumonia prediction tool using two large NIH-funded cohorts of healthy older adults comprising almost 10,000 patients with 10 years of follow-up and detailed clinical, genetic, and biomarker data. I hypothesize that a risk prediction model incorporating genetic and plasma biomarkers with detailed clinical information will outperform models based on simple clinical data alone. Rich as these datasets are, they lack markers of immune cell function, which could be very important in CAP susceptibility. Therefore, in my second aim, I will conduct preliminary experiments to explore the role of neutrophil function in CAP susceptibility. I will test the hypothesis that older adults with CAP have impaired neutrophil function. I will also conduct a functional genomics experiment to test the hypothesis that plasminogen activator inhibitor (PAI-1) genetic variants, associated with increased PAI-1 expression and increased risk of CAP in my preliminary work, influence neutrophil function. Aim 1 leverages resources of existing NIH cohorts to develop a clinically relevant risk prediction tool to target future prevention efforts. Aim 2 will generate preliminary data to incorporate novel functional assays in future prediction efforts and provide a functional basis for genetic markers that increase risk of CAP in gene-association studies. Together, these aims are also designed to provide valuable research practicums for my training as a translational researcher. PUBLIC HEALTH RELEVANCE Relevance for lay audience-Pneumonia is the most common infection and leading cause of death in the United States. A key problem is that we have only a crude notion of who will develop pneumonia to target preventive measures. The goal of this study is to develop a risk prediction tool based on a clinical exam and blood tests that could be done as part of a routine check-up to identify individuals at high risk for pneumonia. [unreadable] [unreadable] [unreadable]